Synthetic method for a chiral 3-(substituted-phenyl)-4-(3-hydroxypropyl)cyclohexanol

ABSTRACT

Racemic endo- and exo-1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylic acids are starting materials for a novel and efficient synthesis of chiral 3R-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4R-(3-hydroxypropyl)-1R-cyclohexanol, a compound having valuable central nervous system (CNS) activity, particularly as an analgesic and as an antiemetic.

BACKGROUND OF THE INVENTION

The present invention concerns a novel, improved method for thesynthesis of3R-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4R-(3-hydroxypropyl)-1R-cyclohexanol,a chiral compound having valuable central nervous system (CNS) activity,particularly as an analgesic and as an antiemetic. The startingmaterials for this convenient and efficient synthetic method are racemicendo- and exo-1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylic acids. Thelatter compounds are readily synthesized from the corresponding methylesters, commercially available as a mixture of the endo and exo isomers.

3R-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-4R-(3-hydroxypropyl)-1R-cyclohexanolhas been previously described as the highly active levorotatory isomer(enantiomer A) ofcis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-trans-4-(3-hydroxypropyl)cyclohexanolin Johnson et al., U.S. Pat. No. 4,371,720, which fully discloses how touse that compound, hereinafter referred to as CP-55,940.

Heretofore, CP-55,940 was synthesized from 3-ethoxy-2-cyclohexenone byone or the other of the following routes, where R^(a) =--CH₂ CH═CH₂ or--(CH₂)₃ OCH₂ C₆ H₅ and R^(b) = ##STR1## Either synthetic route requiresmany chemical steps, with resultant low over-all yields. Becauseresolution to the desired enantiomer occurs very late in the synthesis,these earlier processes are particularly wasteful.

The present invention includes as one step in the process, an unusualrearrangement of a chiral (C₁ -C₃)alkyl1-hydroxybicyclo[2.2.2]oct-5-en-2-carboxylate to a chiral4-(2-carbalkoxyethyl)-2-cyclohexenone. Birch et al. have previouslydescribed a somewhat related rearrangement of racemic methyl1-hydroxy-4-methylbicyclo[2.2.2]oct-5-ene-2-carboxylate into4-(2-carbethoxyethyl)-4-methyl-2-cyclohexenone, J. Chem. Soc. (C), pp.125-126 (1967).

The present invention also encompasses specific chiral compounds of theformulae (10) and (11) below. These compounds are generally disclosed,without reference to chirality or to their use as intermediates, in theabove referenced Johnson et al. U.S. Patent.

SUMMARY OF THE INVENTION

The present invention concerns a process for the preparation of (C₁-C₃)alkyl S-3-[4-(2-cyclohexenone]propionate which comprises thesequential steps of:

(a) resolution of racemic (±)-endo- or(±)exo-1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylic acid bycrystallization of (+)-ephedrine salt of (-)-endo- or (-)-ephedrine saltof (-)-exo-1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylic acid from asolvent;

(b) aqueous acid treatment of said (+)- or (-)-ephedrine salt to produce(-)-endo- or (-)-exo-1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylic acid;

(c) esterification of said (-)-endo- or (-)-exocarboxylic acid with a(C₁ -C₃)alkanol to produce (C₁ -C₃)alkyl (-)-endo- or(-)-exo-1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylate;

(d) demethylation of said (-)-endo- or (-)-exo-methoxycarboxylate by theaction of boron tribromide to produce (C₁ -C₃)alkyl (+)-endo- or(-)-exo-1-hydroxybicyclo[2.2.2]oct-5-ene-2-carboxylate; and

(e) base catalyzed rearrangement of said (+)-endo- or(-)-exohydroxycarboxylate to produce saidS-3-[4-(2-cyclohexenone)]propionate.

The present invention further comprises:

(f) reaction of said (C₁ -C₃)alkyl S-3-[4-(2-cyclohexenone)]propionatewith a 2-benzyl-4-(1,1-dimethylheptyl)phenyl magnesium halide in thepresence of a catalytic amount of a cuprous salt in a reaction inertsolvent to produce (C₁ -C₃)alkyl3-[[4R-[3R-((2-benzyloxy-4-(1,1-dimethylheptyl)phenyl))cyclohexanone]]]propionate;

(g) mild hydride reduction of said (C₁ -C₃)alkyl3-[[4R-[3R-((2-benzyloxy-4-(1,1-dimethylheptyl)phenyl))cyclohexanone]]]propionateto (C₁ -C₃)alkyl3-[[4R-[3R-((2-benzyloxy-4-(1,1-dimethylheptyl)phenyl))-1R-cyclohexanol]]]propionate;and

(h) strong hydride reduction of said (C₁ -C₃)alkyl3-[[4R-[3R-((2-benzyloxy-4-(1,1-dimethylheptyl)phenyl))-1R-cyclohexanol]]]propionateto produce3R-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4R-(3-hydroxypropyl)-1R-cyclohexanol.

The last named compound is a known, chiral intermediate, which isconverted to CP-55,940 by known methods (as summarized and referencedabove).

As used herein, the expression "reaction-inert solvent" is intended tospecify a solvent which does not interact with the starting material(s),reagent(s), intermediate(s) or product(s) of a reaction in a mannerwhich significantly reduces the yield of the desired product(s).

Bicyclo[2.2.2]octene intermediates of the present invention are of thefollowing stereochemical formulae:

    ______________________________________                                         ##STR2##                                                                                       ##STR3##                                                    endo                 exo                                                      ______________________________________                                        (1)   R = H, R.sup.1 = CH.sub.3 ;                                                                  (5)     R = H, R.sup.1 = CH.sub.3 ;                            (+)-ephedrine salt     (-)-ephedrine salt                               (2)   R = H, R.sup.1 = CH.sub.3                                                                    (6)     R = H, R.sup.1 = CH.sub.3                        (3)   R = (C.sub.1 -C.sub.3)alkyl,                                                                 (7)     R = (C.sub.1 -C.sub.3)alkyl,                           R.sup.1 = CH.sub.3     R.sup.1 = CH.sub.3                               (4)   R = (C.sub.1 -C.sub.3)alkyl,                                                                 (8)     R = (C.sub.1 -C.sub.3)alkyl,                           R.sup.1 = H            R.sup.1 = H                                      ______________________________________                                    

Further valuable intermediates of the present invention are of thestereochemical formulae ##STR4## In the above summarized processes andintermediates, the preferred (C₁ -C₃)alkyl group is ethyl.

DETAILED DESCRIPTION OF THE INVENTION

The purified racemic endo- andexo-1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylic acids required asstarting materials for the process of the present invention are readilyprepared from commercially available mixed exo/endo isomers of methyl1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylate. Exemplary methods aredetailed below under Preparations 1-3.

Step (a), resolution of (±)-endo- or(±)-exo-1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylic acid with(+)-ephedrine or (-)-ephedrine, respectively, is readily carried out bycontacting substantially one equivalent each of the appropriatecarboxylic acid and ephedrine in a solvent which will separatelydissolve at least a portion of the acid and the ephedrine (with warmingif necessary) and which will crystallize the desired diastereomeric(+)-ephedrine salt of the (-)-endo acid or the (-)-ephedrine salt of the(-)-exo acid respectively, while leaving the undesired diastereomericsalt in solution. Although other suitable solvents may be identified byexperimentation, ethyl acetate has been found to be a solventparticularly well suited for the present purpose. In either case theracemic acid and the chiral ephedrine are preferably combined in warmethyl acetate (50°-90° C.), conveniently at reflux. The desireddiastereomeric salt is recovered by filtration, preferably after coolingto 15°-30° C. and a period of granulation. The desired enantiomericacid, of the formula (2) or (5) respectively, is recovered in step (b)by standard methods of aqueous acidification (which dissolves theephedrine, and either precipitates the enantiomeric acid, or forces itinto a water immiscible extraction solvent from which it is recovered byevaporation). If desired, the optically active ephedrine base isrecovered from mother liquors or raffinates by standard methods, forreuse in the resolution of additional acid.

In step (c), the enantiomeric acid, of the formula (2) or (5), isesterified by standard methods to form a (C₁ -C₃)alkyl ester, of theformula (3) or (6), respectively. For example, the acid is taken intoexcess of the appropriate (C₁ -C₃)alkanol in the presence of a strongacid catalyst (e.g., 10-12 mole % of p-toluene-sulfonic acid).Temperature is not critical; while 30°-80° C. is generally suitable,reflux temperature of the (C₁ -C₃)alkanol is particularly convenient.Alternatively, esterification is accomplished by activation of the acidas an acid chloride or mixed anhydride, or by use of a dehydrating agentsuch as dicyclohexylcarbodiimide, or carbonyldiimidazole. Theintermediate ester product is recovered by standard methods (e.g.,evaporation, extraction, precipitation).

In step (d), the methyl ether group of compounds (3) or (6) is convertedto the 1-hydroxy group, forming compounds of the formula (4) or (7),respectively. This conversion is accomplished under anhydrous conditions(thus avoiding ester hydrolysis) by contact with substantially one molarequivalent of a Lewis acid (e.g., BBr₃ is particularly well-suited forthis purpose), usually in the presence of a reaction-inert solvent(methylene chloride being particularly well-suited) at reducedtemperature (e.g., 0° to -60° C., preferably and conveniently -20° to-30° C.). Intermediate product is readily recovered, e.g., byneutralization of acids with excess of a weak base (e.g., aqueousNaHCO₃), extraction into a water immiscible organic solvent (e.g., themethylene chloride which may have been used as reaction-inert solvent),and evaporation.

Step (e) converts either the (+)-endo-carboxylate or the(-)-exo-carboxylate, of the formulae (4) and (8) respectively, to thesame chiral (C₁ -C₃)alkyl 3-[4-(2-cyclohexenone)]propionate of theformula (9). This unusual rearrangement is readily accomplished in areaction-inert solvent with a strongly basic catalyst, preferably int-butanol, in the presence of a catalytic amount of potassium t-butoxide(e.g., 5 mole %) at 0°-50° C., conveniently at ambient temperature. Theintermediate product is recovered by standard methods, e.g., by mildlyacidic neutralization (e.g., with aqueous pH 6.0 buffer), extractioninto an immiscible organic solvent, and evaporation.

To derive the ultimately desired CP-55,940 requires reduction of theketone group to an alcohol, reduction of the ester group to alcohol, anddebenzylation. The reduction of ketone can be accomplished by use ofstrong hydride reducing agent (also reducing the ester, as describedbelow) or by hydrogenation over a noble metal catalyst (with concurrentdebenzylation). In terms of achieving the desired stereospecifity,however, it is preferred to first selectively reduce the carbonyl groupwith a mild hydride reducing agent, yielding the chiral alcohol ester ofthe formula (11). The reagent of particular value for this purpose isNaBH₄, preferably reacted at reduced temperature (-40° to -75° C.) in areaction inert solvent which contains a hydroxylic component and asecond component which will maintain liquidity of the solvent at thereduced temperature of the reaction. Particularly well suited is amixture of methanol and tetrahydrofuran (THF).

In the preferred embodiment of the present invention, the chiralalcohol-ester (11) is then reduced to the known CP-55,940 precursor:##STR5## with a strong hydride reducing agent, in a reaction inertsolvent. The preferred reagent for this purpose is LiAlH₄ and thepreferred solvent is THF. Temperature is not critical, the range 0°-50°C. being preferred.

The known precursor (12) is converted to CP-55,940 by hydrogenation overa noble metal catalyst, according to the known methods referenced andsummarized above.

The present invention is illustrated by the following examples. However,it should be understood that the invention is not limited to thespecific details of these examples. All temperatures recorded are indegrees Centigrade (°C.).

PREPARATION 1 1-Methoxybicyclo[2.2.2]oct-5-ene-2-carboxylic Acid (Mixedexo/endo Isomers)

In a 3 liter flask equipped with a mechanical stirrer, thermometer,reflux condenser, addition funnel and N₂ atmosphere, potassium hydroxide(4.59 mole) was dissolved in methanol (1 L). To the resulting hotsolution was added, over a five minute period, methyl1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylate (1.53 mole) and theresulting light brown solution was heated to reflux for 5 hours. Thereaction was then diluted with H₂ O (700 ml) and stripped under reducedpressure to a tan slimy solid. This solid was dissolved in fresh H₂ O (1L) and washed with methylene chloride (1×500 ml). The separated aqueouslayer was acidified to pH 1.5 with 420 ml conc. HCl at reducedtemperature and extraced with methylene chloride (3×500 ml). Thecombined organic layers were washed with H₂ O (1 L) and brine. Dryingand stripping under reduced pressure yielded 87.8% of title product asbrown solids; mp 77°-81°; pnmr/CDCl₃ /TMS/delta 1.65-2.0 (m,6,C₃ H,C₇H,C₈ H), 2.6-2.8 (m,2,C₄ H, C₂ H), 3.4 (s, 3,OCH₃), 6.2 (m,2,C₅ H,C₆ H).

PREPARATION 2 Iodolactone from1-Methoxybicyclo[2.2.2]oct-5-ene-2-carboxylic Acid and Recovery ofUnreactive Racemic 1-methoxybicyclo[2.2.2]oct-5-ene-2-[exo]carboxylicAcid

In a reactor equipped with a mechanical stirrer, thermometer, additionfunnel and protected from light, title product of the precedingPreparation (1.32 mole) was dissolved in a mixture of sodium bicarbonate(2.89 mole), H₂ O (5 L) and 1N sodium hydroxide (263 ml). The resultingtan solution was then treated with a solution of H₂ O (1.5 L), potassiumiodide (2.89 mole) and iodine (1.45 mole) yielding a brown suspensionwhich was stirred at ambient temperature for 22 hours. The reaction wasthen diluted with methylene chloride (1.5 L) and, after stirring for 1.0hour, was separated and the aqueous phase extracted with fresh methylenechloride. The combined organic extracts were washed with sodiumthiosulfate (20% solution, 2×2000 ml), sodium bicarbonate (1×2 L of 20%solution), H₂ O (1×1 L). Drying, treating with activated carbon andstripping under reduced pressure gave title iodolactone as an orangesolid in 83.15% yield [adjusted for recovered exo-acid below]; mp125°-126°; ir (KBr) 1781 cm⁻¹ ; pnmr/CDCl₃ /TMS/delta 4.9 (d,1,C₆ H),4.5 (m,1,C₅ H), 3.25 (s,3,OCH₃), 2.9-2.0 (m,7).

The unreacted title exo-acid was isolated by acidifying the basicaqueous layer from the reaction with conc. HCl, extracting withmethylene chloride (2×1.5 L) and washing the combined organic layerswith sodium thiosulfate (2×2 L of 20% aqueous solution) and H₂ O (2×2L). Drying and stripping under reduced pressure yielded a yellow solidaccounting for 21.7% of the starting diastereomeric acid mixture; mp99°-103°; ir (KBr) 1705 cm⁻¹ ; pnmr/CDCl₃ /TMS/delta 6.3 (m,2, olefinicCH), 3.4 (s,3,OCH₃), 2.9-2.4 (m,2,CH), 2.2-1.2 (m,6,CH₂).

PREPARATION 3 Racemic1-Methoxybicyclo[2.2.2]oct-5-ene-2-[endo]carboxylic acid

In a 5 L reactor equipped with reflux condenser, thermometer, mechanicalstirrer and N₂ atmosphere, a suspension of title iodolactone of thepreceding Preparation (0.863 mole) in ethanol (2.5 L) at 22° C. wastreated with zinc dust (1.29 mole) added portionwise. The resulting graysuspension was heated at reflux for 3.0 hours and then allowed to coolto room temperature, filtered through a diatomaceous earth pad under N₂cover and the cake washed with fresh ethanol. The yellow filtrate wasstripped under reduced pressure to white solids which were partitionedbetween methylene chloride (1 L) and 2N HCl (1 L). The separated aqueousphase was extracted with fresh methylene chloride (500 ml). The combinedorganic layers were overlaid with H₂ O (500 ml), made basic with 15%sodium hydroxide, further diluted with H₂ O and the layers separated.The latter product rich aqueous layer was washed with methylene chloride(500 ml), acidified (conc. HCl), and extracted with fresh methylenechloride (1×1 L, 2×500 ml). The latter organic layers were combined,back-washed with H₂ O (500 ml) and brine, dried and stripped underreduced pressure to produce title product as white solids in 94.1%yield; mp 80°-82°; pnmr/CDCl₃ /TMS/delta 6.2 (m,2,olefinic CH), 3.4(s,3,OCH₃), 2.8 (t,1, J₂,3=7 Hz), 2.6 (m,1,C₄ H), 1.9-1.6 (m,6,CH₂).

EXAMPLE 1 (+)-Ephedrine Salt of(-)-1-Methoxybicyclo[2.2.2]oct-5-ene-2-[endo]carboxylic acid (1)

In a reactor equipped with a mechanical stirrer, reflux condenser andaddition funnel, the racemic endo acid of the preceding Preparation(0.976 mole) was dissolved in refluxing ethyl acetate (1 L). A solutionof (+)-ephedrine (0.976 mole) in warm ethyl acetate (500 ml) was addedover a 15 minute period. After refluxing 10 more minutes, the reactionmixture was allowed to cool to ambient temperature, during which solidsprecipitated. After granulating for 18 hours, crude title product wasrecovered by filtration, mp 109°. Recrystallization from hot ethylacetate gave purified title product, 76.8% of theory, mp 129°-130°;[alpha]_(D) ²⁵ +14.25° (C=1.06, CH₃ OH); pnmr/CDCl₃ /TMS/delta 8.1(s,3,hetero H), 7.2 (m,5,aromatic CH), 6.2 (d,2,olefinic CH), 5.2(d,1,benzylic CH), 3.3 (s,3, OCH₃), 3.1-2.3 (m) and 2.6 (s,N--CH₃) 5Htotal, 2.0-1.3 (m,6,CH₂), 1.0 (d,3,CH₃).

Analysis: Required: C₂₀ (69.14%) H₂₉ (8.41%) N(4.03%). Actual: C(69.25%)H(8.48%) N(4.09%).

EXAMPLE 2 (-)-1-Methoxybicyclo[2.2.2]oct-5-ene-2-[endo]carboxylic Acid(2)

Title free acid was liberated by treating the salt of the precedingExample (0.0288 mole) in methylene chloride (100 ml) with 20% aqueousHCl (50 ml) vigorously stirred for 1.0 hour. The layers were separatedand the aqueous extracted with fresh methylene chloride. The combinedorganic layers were washed with 1N HCl and brine. Drying and strippingunder reduced pressure gave title product as a colorless oil whichcrystallized on standing; 94% yield; mp 57°-60°; ir (KBr) 1704 cm⁻¹ ;[alpha]_(D) ²⁵ -24.95° (C=1.04,CH₂ Cl₂); pnmr/CDCl₃ /TMS/delta 6.2(m,2,olefinic CH), 3.5 (s,3,OCH₃), 2.85 (t,1,C₂ H), 2.6 (m,1,C₄ H),2.0-1.5 (m,6,CH₂).

EXAMPLE 3 (-) Ethyl 1-Methoxybicyclo[2.2.2]oct-5-ene-2-[endo]carboxylate[(3,R=ethyl)]

In a reactor equipped with reflux condenser and N₂ atmosphere, theresolved (-) endo-acid of the preceding Example (0.0247 mole),p-toluenesulfonic acid (2.47 mmole) and ethanol (60 ml) were combinedand refluxed for 20 hours. The reaction mixture was stripped underreduced pressure to a yellow oil which was partitioned between H₂ O andmethylene chloride. The separated organic layer was washed withsaturated aqueous sodium bicarbonate, 1N HCl and brine. Drying andstripping under reduced pressure gave title product as a light yellowoil in 80% yield; pnmr/CDCl₃ /TMS/delta 6.1 (m,2,olefinic CH), 4.0 (q,2,J=7 Hz), OCH₂ CH₃), 3.3 (s,3,OCH₃), 2.8 (m,1,C₂ H), 2.5 (m,1,C₄ H),2.0-1.4 (m,6,CH₂), 1.2 (t,3,J=7 Hz, OCH₂ CH₃); ir (KBr) 1725 cm⁻¹ ;[alpha]_(D) ²⁵ -6.18°.

EXAMPLE 4 (+) Ethyl 1-Hydroxybicyclo[2.2.2]oct-5-ene-2-[endo]carboxylate[(4), R=ethyl]

Title product of the preceding Example (0.1 mole) was dissolved inmethylene chloride (210 ml) and cooled to -30°. By dropwise addition, amethylene chloride solution of boron tribromide (100 ml of 1M) was addedover a 15 minute period maintaining a reaction temperature of -30° to-25°. The resulting yellow solution was stirred at -25° to -20° for 1hour, then carefully poured, under N₂ cover, into a mechanically stirredsolution of saturated aqueous sodium bicarbonate and wet ice, stirringfor 30 minutes. The layers were then separated, the aqueous layerextracted with methylene chloride (200 ml) and combined organic layerswashed with H₂ O and brine. Drying and concentrating in vacuo gave 90.3%of the title product as a yellow oil; [alpha]_(D) ²⁵ +35.8° (C=1.08,CHCl₃); ir (CHCl₃) C═O 1709 cm⁻¹ --OH 3669 cm.sup. -1 ; MS P⁺ 196;pnmr/CDCl₃ /TMS/delta 6.05 (d,2,olefinic CH), 4.1 (q over singlet, 3,OCH₂ CH₃ and OH), 2.9-2.4 (m,2,C₂ H,C₄ H), 2.2-1.6 (m,6, CH₂), 1.2(t,3,OCH₂ CH₃).

EXAMPLE 5 (-)-Ephedrine Salt of(-)-1-Methoxybicyclo[2.2.2]oct-5-ene-2-[exo]carboxylic Acid (5)

Racemic 1-methoxybicyclo[2.2.2]oct-5-ene-[exo]carboxylic acid (0.302mole) was dissolved in refluxing ethyl acetate (250 ml) and treated witha solution of (-)-ephedrine (0.302 mole) in warm ethyl acetate (100 ml).The resulting suspension was granulated at room temperature and solidscollected by filtration. Redissolving the solids in hot ethyl acetate(750 ml), then cooling and granulating at room temperature gave purifiedtitle product, 55.9% of theory; mp 135°-136°; [alpha]_(D) ²⁵ -39.55°(C=1.09, CH₃ OH).

EXAMPLE 6 (-)-1-Methoxybicyclo[2.2.2]oct-5-ene-2-[exo]carboxylic Acid(6)

Title salt of the preceding Example (8 mmole) was stirred with methylenechloride (50 ml) and 20% aqueous HCl (25 ml) for 90 minutes. The phaseswere separated and the aqueous extracted with fresh methylene chloride.The combined organic layers were washed with 1NHCl, H₂ O and brine.Drying and concentrating gave title product in 84.9% yield; mp 77°-80°;[alpha]_(D) ²⁵ -108.33° (C=1.01, CH₂ Cl₂); pnmr/CDCl₃ /TMS/delta 6.35(s,1,C₆ H), 6.3 (d,1,C₅ H), 3.5 (s,3,OCH₃), 2.8-2.4 (m,2,C₂ H,C₄ H),2.1-1.2 (m,6,CH₂).

EXAMPLE 7 (-) Ethyl 1-Methoxybicyclo[2.2.2]oct-5-ene-2-[exo]carboxylate[(7), R=ethyl]

A solution of (-) 1-methoxybicyclo[2.2.2]oct-5-ene-2-[exo]carboxylicacid (5.5 mmole) and p-toluenesulfonic acid (0.66 mole) in ethanol (15ml) was heated at reflux for 20 hours. The mixture was stripped underreduced pressure to a clear oil which was partitioned between methylenechloride and H₂ O. The separated aqueous layer was extracted withmethylene chloride and the combined organic layers washed with diluteaqueous sodium bicarbonate, 1N HCl and H₂ O. Drying and concentratinggave title product as a clear oil in 88.3% yield. pnmr/CDCl₃ /TMS/delta6.2 (m,2, olefinic CH), 4.0 (q,2,OCH₂ CH₃), 3.3 (s,3,OCH₃), 2.8-2.4(m,2,C₂ H,C₄ H), 2.1-1.5 (m,6,CH₂), 1.1 (t,3,OCH₂ CH₃).

EXAMPLE 8 (-) Ethyl 1-Hydroxybicyclo[2.2.2]oct-5-ene-2-[exo]carboxylate[(8), R=ethyl]

Title product of the preceding Example (4.8 mmole) in methylene chloride(15 ml) at -25° was treated over a 10 minute period with borontribromidemethylene chloride solution (1M, 4.8 ml). After 1 hour, themixture was poured into saturated aqueous sodium bicarbonate and ice,and stirred until foaming subsided. The layers were separated and theaqueous layer extracted with methylene chloride. The combined organiclayers were then washed with H₂ O, dried and concentrated to providetitle product as a yellow oil in 75.8% yield; pnmr/CDCl₃ /TMS/delta 6.1(m,2, olefinic CH), 4.1 (q,2,J=7 Hz, OCH₂ CH₃), 3.7 (s,1,--OH), 2.6(m,2, C₂ H,C₄ H), 2.2-1.2 (m over t,9,CH₂ and OCH₂ CH₃).

EXAMPLE 9 (+) Ethyl 3-[4(2-Cyclohexenone)]propionate [(9), R=ethyl]Method A

A solution of title product of Example 4 (0.0785 mole) in t-butanol (165ml) was treated with potassium t-butoxide (3.9 mmole) at ambienttemperature. After 45 minutes, the solution was poured into pH 6.0buffer (150 ml) and ethyl acetate, vigorously stirred for 15 minutes andthe layers separated. The aqueous phase was extracted with fresh ethylacetate and the organic layers combined, back-washed with H₂ O andbrine, dried and concentrated to give title product as a light yellowoil in 92.7% yield; [alpha]_(D) ²⁵ +73.84° (C=1.07, CHCl₃); pnmr/CDCl₃/TMS/delta 6.8 (m,1,C₃ H), 6.0 (d of d, 1, C₂ H), 4.1 (q,2,OCH₂ CH₃),2.6-2.2 (m,5), 2.2-1.5 (m,4), 1.2 (t,3,OCH₂ CH₃). The pH 6.0 buffer wasprepared from 4.64 gm KH₂ PO₄, 0.86 gm Na₂ HPO₄, and 200 ml H₂ O.

Method B

A solution of title product of Example 8 (3.3 mmole) in t-butanol (20ml) at room temperature was treated with potassium-t-butoxide (0.166mmole) and stirred for 1 hour. The reaction mixture was then poured intoH₂ O and extracted with ethyl acetate. The separated organic layer waswashed with H₂ O and brine, dried and concentrated to afford titleproduct as a brown oil in 83.9% yield; [alpha]_(D) ²⁵ +67.48° (C=1.11,CHCl₃); pnmr identical with above Method A product.

EXAMPLE 10 Ethyl3-[[4R-[3R-((2-benzyloxy-4-(1,1-dimethylheptyl)phenyl))cyclohexanone]]]propionate(10, R=ethyl)

A solution formed by dissolving 2-benzyloxy-4-(1,1-dimethylheptyl)phenylbromide (0.377 mole) in tetrahydrofuran (30 ml) was added dropwise tomagnesium turnings (0.085 mole) in tetrahydrofuran (30 ml) maintaining agentle reflux. The Grignard was initiated using a small amount of sodiumbis(2-methoxyethoxy)aluminum hydride as catalyst at 65° C. externallyheated. When the addition was complete, the mixture was heated at refluxfor 90 minutes, then gradually cooled to room temperature, and after 60minutes, cooled to -20° C. Maintaining that temperature, title productof the preceding Example (0.068 mole) in THF (40 ml) was added dropwiseover a 20 minute period with simultaneous addition of cuprous iodide(0.0115 mole) in 3 portions. The resulting yellow mixture was stirred at-20° C. for 45 minutes, then quenched by dropwise addition at 0°-10° C.to an aqueous solution of NH₄ Cl (3.23 gm/10 ml) forming a thicksuspension which, on stirring for 15 minutes in air, gave a tan solidsuspended in blue solution. The latter was filtered over diatomaceousearth, with ethyl acetate wash. The combined filtrate and wash wasextracted with H₂ O (50 ml), saturated aqueous ammonium chloride (2×30ml) and brine, dried and conconcentrated in vacuo to a yellow oil. Theoil was chromatographed on silica gel (900 gms) with 10% ethylacetate-hexane as eluant. The product rich fractions were combined andstripped to yield title product as an oil in 40.24% of theory;[alpha]_(D) ²⁵ -20.03° (CHCl₃, C=2.521).

EXAMPLE 11 Ethyl3-[[4R-[3R-((2-benzyloxy-4-(1,1-dimethylheptyl)phenyl))-1R-cyclohexanol]]]propionate(11, R=ethyl)

To a solution formed by combining title product of the preceding Example(0.0175 mole), tetrahydrofuran (40 ml) and methanol (70 ml) at -65° C.,there was added (in 4 charges) sodium borohydride (0.02 mole). Afterstirring for 1.5 hours at -50° C., the reaction was poured into H₂ O at0° C. and stripped to about half volume. Extracting with ethyl acetate(1×50 ml, 1×25 ml), washing the combined organic layers with brine,drying and evaporation in vacuo gave a yellow viscous oil. The oil waspurified by column chromatography using silica gel support (325 gms) andeluting with 10% ethyl acetate-hexanes, monitoring by TLC (2:1ether:hexane). Title product was isolated in 46.5% yield; [alpha]_(D) ²⁵-25.62° [C=1.05, CHCl₃ ]; pnmr/CDCl₃ /TMS/delta: 7.4 (s,5H); 5.15(s,2H9; 3.85-4.4 (m,q,4H); 0.8-2.3 (m,29H).

EXAMPLE 123R-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4R-(3-hydroxypropyl)-1R-cyclohexanol(12)

To a THF solution (35 ml) of title product of the preceding Example (7.4mmole) at -5° C., lithium aluminum hydride (7.4 mmole) was addedportionwise over 10 minutes. The reaction was stirred at 0° for 1 hour;room temperature for 1 hour and reflux for 1.5 hours. Fresh lithiumaluminum hydride (3.7 mmole) was added and reflux continued for 1 hour.The reaction, which solidified on cooling to room temperature, wasfurther cooled to 0°-5° C. and diluted with ethyl acetate (30 ml) toform a gray suspension. The latter was carefully added to H₂ O (30 ml),maintaining pH 5.5 with 1N HCl. The mixture was then filtered throughdiatomaceous earth. The aqueous layer was separated from the filtrateand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried and stripped in vacuo to yield title product asa clear oil, identical with enantiomer A of U.S. Pat. No. 4,371,720,cited above. That same patent document provides specific procedures forconverting title product to CP-55,940.

Title product was further characterized by conversion to itsbis-d-mandelate ester. Title product (4.9 mmole), d-mandelic acid (10.9mmole), benzene (35 ml) and p-toluenesulfonic acid (0.1 mmole) werecombined and refluxed for 20 hours, collecting the H₂ O produced in aDean-Stark trap. The reaction mixture was cooled to room temperature andpoured into dilute NaHCO₃. The aqueous layer was separated and extractedwith ethyl acetate. The combined organic layers were washed with diluteNaHCO₃, then H₂ O, dried and stripped to a tan oil, which wascrystallized from isopropyl ether, 38.6% yield; mp 107°-108° C.;[alpha]_(D) ²⁵ +30.24° (C=1.035, CHCl₃); pnmr/CDCl₃ /TMS/delta includes7.3 (2s); 6.8 (m).

I claim:
 1. A carbohexacyclic compound having the stereochemical formula##STR6## wherein R is (C₁ -C₃)alkyl.
 2. The compound of claim 1 whereinR is ethyl.
 3. The compound of claim
 2. having the formula (IV).
 4. Thecompound of claim
 2. having the formula (V).
 5. A carbohexacycliccompound having the stereochemical formula ##STR7## wherein R is (C₁-C₃)alkyl.
 6. A compound of claim 5 wherein R is ethyl.
 7. A process forthe preparation of (C₁ -C₃)alkyl S-3-[4-(2-cyclohexenone]propionatewhich comprises the sequential steps of:(a) resolution of racemic(±)-endo- or (±)-exo-1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylic acidby warming said racemic endo- or exo-compound to 50-90 C. withsubstantially one molar equivalent of (+)-ephedrine or (-)-ephedrine,respectively, in a solvent; and recovering crystalline (+)-ephedrinesalt of (-)-endo- or (-)-ephedrine salt of(-)-exo-1-methoxybicyclo[2.2.2]-oct-5-ene-2-carboxylic acid,respectively; (b) aqueous acid treatment of said (+)- or (-)-ephedrinesalt to produce (-)-endo- or(-)-exo-1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylic acid; (c)esterification of said (-)-endo- or (-)-exo-carboxylic acid with a (C₁-C₃)alkanol to produce (C₁ -C₃)alkyl (-)-endo- or(-)-exo-1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylate; (d)demethylation of said (-)-endo- or (-)-exo-methoxycarboxylate by theaction of one molar equivalent of boron tribromide in a reaction-inertsolvent at 0° to -60° C. to produce (C₁ -C₃)alkyl (+)-endo- or(-)-exo-1-hydroxybicyclo[2.2.2]oct-5-ene-2-carboxylate; and (e)rearrangement of said (+)-endo- or (-)-exohydroxycarboxylate in areaction inert solvent in the presence of a strongly basic catalyst at0°-50° C. to produce said S-3-[4-(2-cyclohexenone)]propionate.
 8. Aprocess of claim 7 which further comprises reaction of said (C₁-C₃)alkyl S-3-[4-(2-cyclohexenone)]propionate with a2-benzyl-4-(1,1-dimethylheptyl)phenylmagnesium halide in the presence ofa catalytic amount of a cuprous salt in a reaction inert solvent toproduce (C₁ -C₃)alkyl3-[[4R-[3R-((2-benzyloxy-4-(1,1-dimethylheptyl)phenyl))cyclohexanone]]]propionate.9. A process of claim 8 which further comprises mild hydride reductionof said (C₁ -C₃)alkyl3-[[4R-[3R((2-benzyloxy-4-(1,1-dimethylheptyl)phenyl))cyclohexanone]]]propionateto (C₁ -C₃)alkyl3-[[4R-[3R-((2-benzyloxy-4-(1,1-dimethylheptyl)phenyl))-1R-cyclohexanol]]]propionate.10. A process of claim 8 which further comprises strong hydridereduction of said (C₁ -C₃)alkyl3-[[4R-[3R((2-benzyloxy-4-(1,1-dimethylheptyl)phenyl))-1R-cyclohexanol]]]propionateto produce3R-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4R-(3-hydroxypropyl)-1R-cyclohexanol.11. The process of claim 7 wherein the (C₁ -C₃)alkyl group is ethyl. 12.The process of claim 8 wherein the (C₁ -C₃)alkyl group is ethyl.
 13. Theprocess of claim 9 wherein the (C₁ -C₃)alkyl group is ethyl.
 14. Theprocess of claim 10 wherein the (C₁ -C₃)alkyl group is ethyl.